Generation of transgenic marmosets using a tetracyclin-inducible transgene expression system as a neurodegenerative disease model

Ikuo Tomioka, Naotake Nogami, Terumi Nakatani, Kensuke Owari, Naoko Fujita, Hideyuki Motohashi, Osamu Takayama, Kentaro Takae, Yoshitaka Nagai, Kazuhiko Seki

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Abstract

Controllable transgene expression systems are indispensable tools for the production of animal models of disease to investigate protein functions at defined periods. However, in nonhuman primates that share genetic, physiological, and morphological similarities with humans, genetic modification techniques have not been well established; therefore, the establishment of novel transgenic models with controllable transgene expression systems will be valuable tools to understand pathological mechanism of human disease. In the present study, we successfully generated transgenic marmosets using a tetracyclin-inducible transgene expression (tet-on) system as a neurodegenerative disease model. The mutant human ataxin 3 gene controlled by the tet-on system was introduced into marmoset embryos via lentiviral transduction, and 34 transgene-introduced embryos were transferred into the uteri of surrogate mothers. Seven live offspring (TET1-7) were obtained, of which four were transgenic. Fibroblasts from TET1 and 3 revealed that inducible transgene expression had occurred after treatment with 10 μg/mL of doxycycline, while treatment with doxycycline via drinking water resulted in 1.7- to 1.8-fold inducible transgene expression compared with before treatment. One transgenic second-generation offspring (TET3-3) was obtained from TET3, and doxycycline-inducible transgene expression in its fibroblasts showed that TET3-3 maintained a high transgene expression level that matched its parent. In conclusion, we established anovel transgenic marmoset line carrying the mutant human ataxin 3 gene controlled by the tet-on system. The development of nonhuman primate models with controllable transgene expression systems will be useful for the identification of disease biomarkers and evaluation of the efficacy and metabolic profiles of therapeutic candidates.

Original languageEnglish
Pages (from-to)772-780
Number of pages9
JournalBiology of Reproduction
Volume97
Issue number5
DOIs
Publication statusPublished - Nov 1 2017
Externally publishedYes

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Keywords

  • Gene regulation
  • Intracytoplasmic sperm injection (ICSI)
  • Primates
  • Transgenesis
  • Transgenic/knockout model

ASJC Scopus subject areas

  • Cell Biology

Cite this

Tomioka, I., Nogami, N., Nakatani, T., Owari, K., Fujita, N., Motohashi, H., Takayama, O., Takae, K., Nagai, Y., & Seki, K. (2017). Generation of transgenic marmosets using a tetracyclin-inducible transgene expression system as a neurodegenerative disease model. Biology of Reproduction, 97(5), 772-780. https://doi.org/10.1093/biolre/iox129